Solid oral drug compositions or preparations have various release profiles such as a modified or extended release profile as referenced by USP XXIII (CDER, FDA, Rockville, Md.) or an immediate release profile as referenced by FDA guidelines (Dissolution Testing of Immediate Release Solid Oral Dosage Forms, issued August 1997, Section IV-A). For example, in the dissolution testing guideline for modified release profiles, material dissolves over an extended period and its dissolution is measured over time. A minimum of three time points is recommended and should cover early, middle and late stages of the dissolution profile. The last measurement should be at a time point where at least 80% of the drug is dissolved (Guidance for Industry, “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations”, Food and Drug Administration, CDER, September 1997, Page 17). Adequate sampling should be performed, for example, at 1, 2 and 4 hours and every two hours thereafter until 80% of the drug is released (Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms,” Food and Drug Administration, CDER, September 1997, Page 6). The preferred dissolution apparatus is USP apparatus I (basket) or II (paddle), used at compendially recognized rotation speeds, e.g., 100 rpm for the basket and 50-75 rpm for the paddle (Guidance for Industry, “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations”, Food and Drug Administration, CDER, September 1997, Page 4).
Modified release solid oral dosage forms permit the sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals and/or to modify other pharmacokinetic properties of the active ingredient. Immediate release solid dosage forms permit the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible. A multiphase release profile (i.e., a composition containing at least an immediate release formulation and at least one modified release formulation) may be employed to attain one or more combinations of release rates to attain more specific therapeutic objectives such as a portion of drug releasing immediately, followed by an extended release. However, modulation of the release rate of an active ingredient does not necessarily ensure that long-lasting effective blood level concentrations will be consistently achieved or that the pharmacological effect will be based solely on the release of the drug.
Sustained release formulations for drugs have become increasingly available. This is true especially when the particular drug is relatively soluble. Various formulation techniques have been used for providing a sustained release formulation of soluble drugs. In many such formulations, a drug-containing particle is coated by one or more release retardant layers or films or is dispersed within a continuous matrix such as a polymeric matrix. The coating layer or the matrix comprises a relatively insoluble material or materials, and the release of the drug is controlled by means of the resistance of the coating layer or matrix against the diffusion of the drug there through. The release of the drug from such formulations is driven, e.g., by the gradient of the drug concentration resulting from penetration of, e.g., gastric fluid, by diffusion into the formulation.
One or more film-forming polymers may be employed to provide sustained release of the active substance by controlling its rate of diffusion across the film barrier(s). However, such an approach is compromised if, during ingestion of the oral dosage form, the film is prematurely breached, as by chewing, splitting or abrasion, thereby releasing an excessive amount of active ingredient, which can result in undesirable effects from excessive single-shot drug release, and in failure of the dosage form to remain effective for the required duration.
In the more common matrix-controlled release approach, lipophilic substances, e.g., higher alcohols, waxes, or insoluble thermoplastic materials, are employed. The release is controlled by the rate of diffusion of the active ingredient into the surrounding medium and, if the matrix itself is degradable, by the rate of its degradation. One of the disadvantages is that a complete release of drug from the matrix is frequently not achieved in practice. Another drawback is that dose proportionality of the dosage forms is not readily achieved, thus, requiring different compositions for different strengths. Thus, the matrix composition to formulate a 20 mg sustained release dosage form may well be different from the matrix composition to formulate a 40 mg sustained release dosage form.
U.S. Pat. No. 5,382,601 provides solid pharmaceutical dosage forms containing memantine, which exhibit an extended two-phase release profile, with a portion of the drug being released immediately, followed by a sustained release of the remainder. The matrix of this formulation contains both a water-soluble and a water-insoluble salt of casein, preferably sodium and calcium caseinate. However, casein has an unpleasant taste; it is associated with undesirable effect of exacerbating some side effects as disclosed in U.S. Pat. No. 6,413,556; and displays instability in varying pH. Another concern regarding casein is the possibility of Bovine Spongiform Encephalitis (BSE) contamination since casein is an animal-derived milk protein.
A general method of modified release for N-methyl-D-aspartate (NMDA) receptor antagonists was described in U.S. Pat. No. 6,194,000. This method also involves preparing an instant release component and a modified release component to arrive at the final formulation. The patent discloses a pellet (not a bead) consisting of a coated core, the coating being any suitable coating using organic solvent-based systems. However, not all NMDA antagonists act in the same manner, and this patent does not specifically disclose compositions containing memantine.
Currently, a dosing regimen of memantine of twice a day is employed using immediate release tablets. This may be undesirable because patient compliance decreases as the frequency of taking a drug increases. Moreover, administration of an immediate-release tablet can lead to greater frequency of adverse events due to a faster rate of absorption. For pain treatment, it is very important to maintain the pain relief without additional discomfort. There is therefore an existing and continual need for a once a day modified release formulation containing memantine or a pharmaceutically acceptable salt of memantine with reliable slower absorption over a targeted period of time.